Project Summary/Abstract Human polyomaviruses have been implicated in disease arising in multiple organs. In skin, polyomaviruses have been linked to both cancer (Merkel cell carcinoma) and a hair follicle disorder (trichodysplasia spinulosa) which is seen almost uniformly in immunosuppressed patients, and is strongly linked to trichodysplasia-associated polyomavirus (TSPyV). The clinical findings in trichodysplasia spinulosa include numerous minute follicular papules, most commonly on the face, with prominent hyperkeratotic spicules in place of hair shafts. The affected follicles are distended and comprised almost exclusively of hair matrix cells, inner root sheath-like cells, and masses of abnormally keratinizing cells, with a poorly formed or inapparent dermal papilla. Essentially nothing is known about how TSPyV infection leads to these profound alterations in hair follicle biology. In this exploratory proposal, we will use mouse models to gain insight into the mechanisms underlying development of trichodysplasia spinulosa. Specifically, we will test the hypothesis that one or more TSPyV transforming antigens (TAgs) drive aberrant proliferation of hair matrix cells, leading to disproportionate expansion of inner root sheath cells at the expense of cell lineages comprising the hair shaft. We propose to generate Cre-inducible mouse models to express TSPyV TAgs in a spatially and temporally restricted manner in adult mice. We will characterize resultant changes in proliferation, cell death, and lineage marker expression; and screen for alterations in candidate signaling pathways. The proposed studies will yield novel insight into the molecular and cellular basis of trichodysplasia spinulosa and may identify new targets for therapeutic intervention.